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Newborn screening is designed to identify infants with treatable rare disorders at birth in order to start therapies before the infants get sick. These disorders can lead to developmental disability, growth failure, liver disease, seizures, and even death if untreated. The investigation of potential new candidate disorders for screening, evaluation of new screening tests or improvement of existing methods, and the measurement of the long-term effectiveness of screening to improve health are all active aspects of my research.

We have a focus on disorders affecting the use of fats as an energy source and a variant of one of these disorders that is common to coastal BC First Nations. This variant is associated with an increased risk of infant death, but may also have benefits related to traditional diets.. Investigation of this variant will lead to a better understanding of its clinical impact and help to identify effective interventions.

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy.American journal of human geneticsLehman A and Thouta S and Mancini GMS and Naidu S and van Slegtenhorst M and McWalter K and Person R and Mwenifumbo J and Salvarinova R and CAUSES Study and EPGEN Study and Guella I and Claydon TDOI: 10.1016/j.ajhg.2017.05.016PubMed: 2866940507/2017

Exome Sequencing and the Management of Neurometabolic Disorders.Tarailo-Graovac M and Shyr C and Ross CJ and Horvath GA and Salvarinova R and Ye XC and Zhang LH and Bhavsar AP and Lee JJ and Drögemöller BI and Abdelsayed M and Alfadhel M and Armstrong L and Baumgartner MR and Burda P and Connolly MB and Cameron J and Demos M and Dewan T and Dionne JDOI: 10.1056/NEJMoa1515792PubMed: 2727656206/2016

The genotypic and phenotypic spectrum of PIGA deficiency.Tarailo-Graovac M and Sinclair G and Stockler-Ipsiroglu S and Van Allen M and Rozmus J and Shyr C and Biancheri R and Oh T and Sayson B and Lafek M and Ross CJ and Robinson WP and Wasserman WW and Rossi A and van Karnebeek CDDOI: 10.1186/s13023-015-0243-8PubMed: 258855272015

Defects in fatty acid amide hydrolase 2 in a male with neurologic and psychiatric symptoms.Sirrs S and van Karnebeek CD and Peng X and Shyr C and Tarailo-Graovac M and Mandal R and Testa D and Dubin D and Carbonetti G and Glynn SE and Sayson B and Robinson WP and Han B and Wishart D and Ross CJ and Wasserman WW and Hurwitz TA and Sinclair G and Kaczocha MDOI: 10.1186/s13023-015-0248-3PubMed: 258857832015

AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset.Armstrong L and Biancheri R and Shyr C and Rossi A and Sinclair G and Ross CJ and Tarailo-Graovac M and Wasserman WW and van Karnebeek CDDOI: 10.1007/s10048-014-0411-3PubMed: 2495842408/2014

Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood.van Karnebeek CD and Sly WS and Ross CJ and Salvarinova R and Yaplito-Lee J and Santra S and Shyr C and Horvath GA and Eydoux P and Lehman AM and Bernard V and Newlove T and Ukpeh H and Chakrapani A and Preece MA and Ball S and Pitt J and Vallance HD and Coulter-Mackie M and Nguyen HDOI: 10.1016/j.ajhg.2014.01.006PubMed: 2453020303/2014

Detection of a novel intragenic rearrangement in the creatine transporter gene by next generation sequencing.Yu H and van Karnebeek C and Sinclair G and Hill A and Cui H and Zhang VW and Wong LJDOI: 10.1016/j.ymgme.2013.09.018PubMed: 2414039812/2013

Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations.Sinclair GB and Collins S and Popescu O and McFadden D and Arbour L and Vallance HDDOI: 10.1542/peds.2011-2924PubMed: 2309034411/2012

Enhanced interpretation of newborn screening results without analyte cutoff values.Marquardt G and Currier R and McHugh DM and Gavrilov D and Magera MJ and Matern D and Oglesbee D and Raymond K and Rinaldo P and Smith EH and Tortorelli S and Turgeon CT and Lorey F and Wilcken B and Wiley V and Greed LC and Lewis B and Boemer F and Schoos R and Marie SDOI: 10.1038/gim.2012.2PubMed: 2276663407/2012

The use of parenteral nutrition for the management of PKU patient undergoing chemotherapy for lymphoma: a case report.Salvarinova-Zivkovic R and Hartnett C and Sinclair G and Dix D and Horvath G and Lillquist Y and Stockler-Ipsiroglu SDOI: 10.1016/j.ymgme.2012.01.007PubMed: 2230585604/2012

Evaluation of two year treatment outcome and limited impact of arginine restriction in a patient with GAMT deficiency.Mercimek-Mahmutoglu S and Dunbar M and Friesen A and Garret S and Hartnett C and Huh L and Sinclair G and Stockler S and Wellington S and Pouwels PJ and Salomons GS and Jakobs CDOI: 10.1016/j.ymgme.2011.09.037PubMed: 2201949101/2012

Infantile cardioencephalopathy due to a COX15 gene defect: report and review.Alfadhel M and Lillquist YP and Waters PJ and Sinclair G and Struys E and McFadden D and Hendson G and Hyams L and Shoffner J and Vallance HDDOI: 10.1002/ajmg.a.33881PubMed: 2141297304/2011

Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.McHugh D and Cameron CA and Abdenur JE and Abdulrahman M and Adair O and Al Nuaimi SA and Åhlman H and Allen JJ and Antonozzi I and Archer S and Au S and Auray-Blais C and Baker M and Bamforth F and Beckmann K and Pino GB and Berberich SL and Binard R and Boemer F and Bonham JDOI: 10.1097/GIM.0b013e31820d5e67PubMed: 2132594903/2011

Treatment of intractable epilepsy in a female with SLC6A8 deficiency.Mercimek-Mahmutoglu S and Connolly MB and Poskitt KJ and Horvath GA and Lowry N and Salomons GS and Casey B and Sinclair G and Davis C and Jakobs C and Stockler-Ipsiroglu SDOI: 10.1016/j.ymgme.2010.08.016PubMed: 2084688912/2010

Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live newborns in Yukon, Northwest Territories, and Nunavut.Collins SA and Sinclair G and McIntosh S and Bamforth F and Thompson R and Sobol I and Osborne G and Corriveau A and Santos M and Hanley B and Greenberg CR and Vallance H and Arbour LDOI: 10.1016/j.ymgme.2010.07.013PubMed: 206966062010

The paradox of the carnitine palmitoyltransferase type Ia P479L variant in Canadian Aboriginal populations.Greenberg CR and Dilling LA and Thompson GR and Seargeant LE and Haworth JC and Phillips S and Chan A and Vallance HD and Waters PJ and Sinclair G and Lillquist Y and Wanders RJ and Olpin SEDOI: 10.1016/j.ymgme.2008.12.018PubMed: 1921781404/2009

Heparin cofactor II-thrombin complex: a biomarker of MPS disease.Randall DR and Colobong KE and Hemmelgarn H and Sinclair GB and Hetty E and Thomas A and Bodamer OA and Volkmar B and Fernhoff PM and Casey R and Chan AK and Mitchell G and Stockler S and Melancon S and Rupar T and Clarke LADOI: 10.1016/j.ymgme.2008.05.001PubMed: 1851131908/2008

Generation of a conditional knockout of murine glucocerebrosidase: utility for the study of Gaucher disease.Sinclair GB and Jevon G and Colobong KE and Randall DR and Choy FY and Clarke LADOI: 10.1016/j.ymgme.2006.09.008PubMed: 1707917502/2007

Heterologous expression and characterization of a rare Gaucher disease mutation (c.481C > T) from a Canadian aboriginal population using archival tissue samples.Sinclair G and Choy FY and Ferreira PDOI: 10.1006/mgme.2001.3215PubMed: 1170886511/2001

A novel complex allele and two new point mutations in type 2 (acute neuronopathic) Gaucher disease.Sinclair G and Choy FY and Humphries LDOI: 10.1006/bcmd.1998.0210PubMed: 985189512/1998

Research

Second-Tier Testing for Newborn ScreeningThe performance of newborn screening programs can be defined by the positive predictive value (PPV) of the screening tests, a major component of which is the false positive rate. Traditional approaches to screening for some disorders have an unacceptable false positive rate, but attempts to minimize this rate by raising screening cutoffs can lead to increased false negative rates and the associated devastating outcomes of a missed case. We have developed a number of second-tier screening tests, sampled from the same original newborn screening bloodspot, as an approach to reduce false positive rates without negatively affecting the sensitivity of testing. Our work involves the development of a number of mass spectrometry-based testing approaches and evaluation of the performance impacts of these tests in routine use. To date, we have implemented second-tier testing for congenital adrenal hyperplasia (CAH) and Maple Syrup Urine Disease (MSUD) and have methods in development for Propionic Acidemia (PA), Methylmalonic Acidemia (MMA), and Homocystinuria (HCY).

GAMT Deficiency ScreeningGuanidinoacetate methyltransferase (GAMT) deficiency is an inherited disorder of creatine biosynthesis that leads to severe neurological complications in affected children. Treatment with supplemental creatine and other dietary restrictions has been shown to be effective when initiated early. This makes GAMT deficiency a potential candidate for newborn screening. We are investigating the carrier frequency for GAMT deficiency in BC to determine a theoretical disease incidence and evaluating the measurement of guanidinoacetate (GAA) in bloodspots as a potential approach to population-wide newborn screening for this treatable disorder.

CPT1a P479L VariantThe carnitine palmitoyltransferase 1A (CPT1a) p.P479L variant has recently been found to be common in coastal First Nations communities in BC and also in aboriginal populations in Alaska, NWT, Nunavut, and Greenland. CPT1a is a central enzyme in fatty acid oxidation and is required for import of fatty acids into the mitochondrion to be utilized as an energy source. This variant (p.P479L) was first identified in individuals with symptoms suggestive of a fatty acid oxidation disorder and has been shown to decrease CPT1a activity in vitro. We have performed a population based retrospective study in BC to confirm that the variant is common to coastal communities and is associated with a small increased risk in sudden unexpected death in infancy. Similar results have been found in Nunavut and Alaska. There is evidence, however, that this variant is also associated with improved plasma lipid profiles and obesity markers in adults suggesting a selective advantage, possibly related to alterations in the regulation of enzyme activity. We are continuing to investigate both the potential harms and benefits of this variant through prospective studies with community participants and basic biochemical investigations using in vitro methods to better understand the biochemical and clinical implications of this common variant.

Kids with the highest blood-sugar levels experienced the most improvement after starting insulin pump treatment, according to new research. The study suggests insulin pump therapy should be considered for children with higher blood sugar levels to help avert some of the lifelong complications of diabetes.

A new study from BC Children’s, UBC and an international team of researchers published in the New England Journal of Medicine is the first to identify a rarely-seen type of DNA mutation as the cause of an inherited metabolic disorder.

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